Spinal anesthesia has obvious advantages. However, spinal anesthesia, using local anesthetics, is associated with acute side effects including hypotension and urinary retention, persistent sequelae like transient neurologic symptoms (TNS) and on occasion permanent deficits like cauda equina syndrome. Current research in spinal anesthesia has focused on the incidence of TNS and the dose and particular local anesthetic used, the effect of additives like epinephrine, and associated factors like patient position. There has been no recent progress in advancing new drugs for spinal anesthesia. This invention moves forward in the direction of new drugs for spinal anesthesia.
One alternative to conduction block for spinal anesthesia is blockade of synaptic transmission in the spinal cored. This could be accomplished by activation of inhibitory receptors or by antagonism of excitatory receptors. Glutamate is the major excitatory central nervous system neurotransmitter. Glutamate activates ionotropic excitatory amino acid (EAA) receptors that are highly prevalent in the nervous system and transmit information through both N-methyl-D-aspartate (NMDA) as well as nonNMDA EAA receptors. Ketamine, a drug used clinically in anesthesia, antagonizes NMDA receptors. Thus far, a clinical use for nonNMDA receptor antagonists, blocking alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and kainate receptors, has not been discovered. In experimental animals, spinally administered non-NMDA receptor antagonists have been shown to inhibit nociception and produce motor dysfunction (Zahn P K, Umali E, Brennan T J: Intrathecal non-NMDA excitatory amino acid receptor antagonists inhibit pain behaviors in a rat model of postoperative pain, Pain 1998; 74: 213-23; Pogatzki E M, Zahn P K, Brennan T J; Effect of pretreatment with intrathecal excitatory amino acid receptor antagonists on the development of pain behavior caused by plantar incision. Anesthesiology 2000; 93: 489-96). This effect likely results from antagonism of nonNMDA receptors on dorsal horn sensory neurons as well as motor neurons in the ventral horn of the spinal cord.
Through drug development, more potent and specific nonNMDA receptor antagonists like 6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinolone-3-carboxylic acid have been discovered. The observations of these literature references are perhaps why new drug investigations have gone in different directions than such specific nonNMDA receptors.
This inventor has discovered a more potent and specific nonNMDA receptor antagonist which is highly effective for spinal anesthesia and without the normal associated acute side effect of hypotension. The specific object of this invention is therefore the development of this spinal anesthetic and its successful use.